Malignant hypertension due to reflux nephropathy in an adolescent (a case report).
Malignant hypertension in an adolescent due to reflux nephropathy (RN) is rare. Here we are presenting such a case unassociated with the usual symptoms of hypertension. The problems of diagnosis, management, prognosis and prevention of RN are discussed with a review of relevant literature.
Reflux nephropathy (RN) as a cause of hypertension and end stage renal disease is being increasingly recognised. It leads to advanced renal failure in 30% of children and in 15-20% of adults. The incidence of hypertension in children with RN ranges from 5 to 30%. It is important to realise that early detection of RN and long-term management of reflux can prevent both hypertension and end stage renal disease. Therefore, there is a need for increased awareness of this entity amongst the practising physicians so that cases are picked up early and by proper therapy adverse sequele of hypertension, chronic renal failure and end stage renal disease are prevented. The importance of carrying out the voiding cystourethrogram (VCUG) in cases of urinary tract infection (UTI) cannot be overemphasised.
A 13-year-old girl was brought with complaints of pain in abdomen, anorexia and deterioration of mental function in the form of impaired scholastic performance and change in behaviour and understanding. There was no history of headache or visual disturbances, dyspnea or focal paresis. As regards the past history, she had history of urinary tract infection at the age of 5 years and Bell's palsy at the age of 9 years with complete recovery. On examination, she had a blood pressure of 200/120 mmg Hg, heaving apex beat and grade II/VI systolic murmer in mitral area. Fundus examination showed Grade 1V retinal changes with haemorrhage and exudate in both eyes. Other systems were normal.
On investigation haemoglobin was found 10.8 gms%, and TLC 12200/cmm. Differential count showed 84% polymorphs and 16% lymphocytes. The ESR was 72 mm at the end of one hr. (Westergreen method). Routine examination of urine showed albumin + + and 2 to 3 pus cells. Urine culture was positive for Escherichia coli., with colony count of 15000/ml. The fasting blood sugar was 92 mg%. Blood urea and creatinine were 22 and 1 mg% respectively. Serum electrolytes were within normal limits. Total serum bilirubin and serum amylase were normal. ASLO titre was normal. Manteoux test was + +.
A routine chest radiograph showed calcification of mediastinal glands and no cardiomegaly. Electrocardiogram revealed left ventricular hypertrophy with left ventricular strain pattern while echocardiography confirmed concentric left ventricular hypertrophy. Ultrasonogram of abdomen was normal with right and left kidney sizes of 9.1 and 9.0 cms respectively. For detailed investigation of hypertension, urinary vanillyl mandelic acid estimation was done and it was 2.2 mg% (normal 13-7.5 mg%). Plasma renin activity was 12.1 mg/ml/hr (normal range: 0.2-2.7 mg/ml/hr.) Patient was subjected to selective renal angiography and selective renal vein renin estimation, Renal angiography was normal and there was no renal artery stenosis. Plasma renin estimation of right and left renal veins were 4.6 and 5.3 mg/ml/hr (normal 1.5 mg/ml/hr.)
As the cause of hypertension was not yet established, intravenous pyclogram (IVP) and then voiding eystourethrogram (VCUG) were done. WP revealed calyceal deformity on right side with thinning out of adjacent corlex suggesting cortical scarring. VCUG demonstrated bilateral vesicouretral reflux of Grade MAV. Ureters were dilated on both sides and there was distortion and club like blurring of the right upper calyx. (See [Figure:1] and [Figure:2])
She was diagnosed as a case of malignant hypertension due to reflux nephropathy, probably of primary and congenital aetiology.
Though Rance et al have reported that in paediatric cases of persistent systemic hypertension 30% are due to reflux nephropathy, in our country, reports of hypertension due to RN are very few. The obvious reason for this is lack of awareness of this entity amongst the physicians and paediatricians and the reluctance on the part of parents to subject their children to the necessary investigation to arrive at the diagnosis. Another possible reason is that routine measurement of blood pressure in children and adolescents are not taken by the physicians. There is also lack of awareness amongst the physicians and parents that urinary tract infection can lead to serious consequence like RN even though patients may apparently appear to be cured as it happened in this case.
In the recent literature, a lot of controversy surrounds the exact aetiopathogenesis of hypertension in RN. In this connection, the role of intra-renal reflux (IRR) should be emphasised,. It has been shown that VUR alone does not lead to renal scarring. Renal scarring occurs only when VUR is associated with IRR. Factors favouring IRR are (i) association of UTI, (ii) association of high pressure VIR, (iii) the anatomical factors like compound and simple papillae. The compound papillae are more susceptible to IRR than simple papillae, due to anatomy of their orifice.
The 'Big Ben' theory proposed by Ransley and Risdon tries to explain the role of UTI in producing renal scarring. This theory proposes that initial UTI leads to IRR into susceptible compound papillae, which in turn leads to renal damage and scar formation. Following the initial events, non-refluxing papillae adjacent to this already damaged papillae get converted into refluxing papillae when there is a high pressure VUR in addition to recurrence of UTI.
How, the renal scarring leads to hypertension are still not thoroughly understood. In this connection the role of plasma renin activity needs to be discussed. In some patients with RN and hypertension the expected age related decrease in PRA, was not observed indicating that high PRA levels are contributing to hypertension. Another important factor is a focal increase in renin secretion and this can be demonstrated by analysing the segmental renal vein PRA. This segmental hyper secretion of renin may not be reflected in the renal vein PRA and yet they may be playing vital role in causing hypertension. Some other authors have given less importance to the segmental hyper secretion of renin and propagate the view that severity of hypertension is related directly to the degree of scarring. However, the effectiveness of captopril in controlling hypertension of reflux nephropathy favours the view that PRA plays in important role in causing the hypertension in RN.
What has been responsible for VUR in the present case? As there is no evidence of bladder hypertrophy and dilatation of lower ureters, secondary reflux due to obstructive uropathy or bladder sphincter dyssynergia is ruled out. The reflux appears to be primary in our case. Whether this primary reflux is due to congenial abnormalities of the ureter and ureter orifices such as low ratio of intra-mucosal ureteric length to orifice diameter (Normal ratio 5: 1), could not be determined in our case as the parents were reluctant for cystoscopy which is necessary to identify such a congenital abnormality. However, severe Grade IV reflux after a relatively mild single UTI and non-dilatation of lower ureters favour congenial aetiology.
For the diagnosis of RN, various imaging techniques have evolved both to demonstrate reflux as well as scarring. IVP can show scarring, but it can be normal in few cases. Dimercaptosuccinic acid (DMSA) scan is more sensitive than IVP in demonstrating scars. It can identify scar up to 2 years before IVI`. For the demonstrating VUR, direct radionucleide cystography has been proposed as a replacement of standard WUG as the amount of radiation is constant for the dose given and this allows continuous monitoring and can detect reflux at any phase of the study. Only exception is in the initial study in a male child where standard WUG is superior in demonstrating detailed morphology of the collecting system, bladder and the urethra.
Medical Management of hypertension and primary reflux nephropathy consists of following plan: (a) Keeping the urine sterile by continuous prophylactic chemotherapy so as to prevent fresh scarring. This is especially relevant in children below 5 years, as after 5 years the fresh searring is infrequent and after 10 years of age it is not likely to occur. Our patient was put on prophylactic chemotherapy with nitrofurantoin successfully. The drugs most commonly used are sulphamethoxozole -trimenthoprim, nitrofurantoin and sulphisoxazole,. The prophylactic dose is one half of therapeutic dose. How long to continue the prophylactic antibiotic therapy? On this subject there are different opinions. Normand and Smellie's have suggested that a long term antibiotics should be continued until two negative WUGs one year apart are obtained. However, there is another view that if the reflux persists, the age of the patient should be an important determinant in deciding about the discontinuation of long-term chemotherapy. In late childhood and adolescent the disappearance of reflux, especially more than Grade III reflux is very much unlikely and in such a situation, chemo prophylaxis may be discontinued and surgery should be considered as a choice.
(b) Hypertension should be treated by drugs, which decrease the renin production as the increased production of renin is shown to be the important factor in pathogenesis of hypertension. Hence captopril is very useful in hypertension. However, other drugs like propronol, methyl dopa have also been found useful.
(c) Episodes of intercurrent infection may occur despite prophylactic chemotherapy. This should be vigorously treated with antibiotics, the type of antibiotics being used depending upon the culture and antibiotic sensitivity.
The role of surgery in the management of RN is beset with controversy. Surgical success rate for elimination of reflux is quiet high for all grades of VUR: 90-100% for Grades I and II, 93-99% for Grade III and 50-60% for Grade IV and V. However it has been shown that milder grades of reflux may disappear if the UTI is prevented. Another important fact is decreased chances of reflux disappearance with medical treatment with advancing age. In a female adolescent with persistent reflux, aggravation is likely to occur due to increased sexual activity or during pregnancy. Taking these above factors into consideration the surgery should be recommended under following circumstances: (1) in Grade V and possible also Grade IV reflux, (2) failure of long term antibiotics to keep the urine sterile or poor compliance by the patient causing recurrent infection. (3) persistence of reflux by late childhood or adolescent despite long term antibiotics. (4) development of new scars while patient is on prophylatic antibiotics. (5) adolescent female who is expecting to become pregnant and still has a persistent reflux. (6) children who have general feeling of ill-health and decreased appetite probably because of reflux and the continuous medication (as observed by RansleyP.G.)
In such children surgery is indicated as it has been observed that general health and appetite improves after correction of reflux.
Surgical correction of primary VUR before any infection occurs should be theoretically ideal preventive treatment but as there is no easy way of diagnosing children who are having primary VUR and as genesis of primary VUR is not precisely known, this type of prophylaxis is impractical.
The present consensus is to subject all children who have UTI to WUG two weeks after the first documented UTI. If this demonstrates VUR, then these children should be studied for evidence of renal scarring either by IVP or DMSA scan. The patients showing VUR with or without demonstrable scarring should be given prophylatic chemotherapy to keep urine sterile (The scar may take several months to be demonstrable either by IVP or DNISA scan.) The children should be periodically evaluated as regards the improvement in VUR and development of new scarring. For such follow up, evaluation by radionucleide scan are preferable than IVP or VCUG with radio opaque dyes; the radiation involved is markedly less.
Primary reflux of more than Grade III may be surgically corrected especially in younger children and infants to prevent the development of focal renal scarring.