Vanita Shah

Autosomal recessive polycystic kidney disease

The clinical features of 55 cases of autosomal recessive polycystic kidney disease (ARPCKD) have been reviewed. Each had evidence of ARPCKD. The outcomes of 87% were known; 24 had died. Twenty-four of 31 were seen between 1980 and 1986; 7 could not be traced. Forty-five percent presented under 1 month; 38% between 1 month and 1 year; and 9 cases over 1 year. Hyponatraemia occurred in 15 out of 19 aged less than 3 months; hypertension occurred in 65%; splenomegaly in 47% of those surviving more than 3 months. Portocaval shunts were done in 5 aged 2–12 years. Thirteen died of renal failure, 6 under 1 year, and 7 between 1 year and 13 years. Life-table survival rates calculated from birth revealed that 86% were alive at 3 months, 79% at 1 year, 51% at 10 years, and 46% at 15 years. Calculations based on patients who survived to 1 year of age showed that 82% were alive at 10 years and 79% at 15 years. These results reveal an improved prognosis for a condition once assumed to be fatal.

Neutrophil activation in the haemolytic uraemic syndrome: free and complexed elastase in plasma

There is evidence of neutrophil involvement in the pathogenesis of the haemolytic uraemic syndrome (HUS), and neutrophil release products are thought to cause endothelial cell damage. Elastase is the major lysosmal proteinase liberated by activated neutrophils. In this study we measured both free and complexed elastase. No free elastase activity could be detected in the plasma of patients with diarrhoea-associated (D+) HUS using a specific substrate. However, there was a marked increase in α1-antitrypsin (α1-AT) complexed elastase as measured by a newly developed enzyme-linked immunosorbent assay not only in D+ HUS, but also in non-diarrhoea-associated (D-) HUS. This finding is independent of either a high polymorphonuclear leucocyte count or renal failure. This increase in bound elastase together with our sequential data which demonstrate raised α1-AT complexed elastase levels early in the disease process further support the theory that neutrophil activation is one of the key events in the pathophysiology of this disorder.

Lymphocyte subpopulations, interleukin-2 and interleukin-2 receptor expression in childhood nephrotic syndrome.

Abnormal T lymphocyte function and reduced interleukin-2 (IL-2) production have been implicated in the pathogenesis of the nephrotic syndrome (NS). We investigated: (1) lymphocyte subpopulations and expression of IL-2 receptor (IL-2R) on T cells using two-colour flow cytometry, (2) serum IL-2 and (3) the soluble component of IL-2R (sIL-2R) in serum, using enzyme-linked immunosorbent assay, in 38 children with NS. All children, except those in remission, had marked proteinuria. They were divided into groups according to renal pathology: (1) steroid-sensitive NS (SSNS) not receiving prednisolone therapy, (2) SSNS on prednisolone, (3) focal segmental glomerulosclerosis (FSGS), (4) SSNS in remission and not receiving prednisolone therapy, (5) congenital NS (CNS). Results were compared with 26 age-matched controls. Total T lymphocytes (CD3) were reduced in groups 1 and 2; CD4 count was reduced in groups 1–4; CD8 count increased in groups 2 and 3; CD8 and CD19 (B lymphocytes) were significantly reduced in group 5. Increased IL-2R expression (CD25) on CD4 lymphocytes was noted in groups 1, 2 and 3 implying activation of these cells. In patients with SSNS, increased serum sIL-2R was recorded during relapse (1,273±497 U/l vs. 913±401 U/l in remission,P<0.005) but free serum IL-2 was not detectable at any stage. The specific alterations in lymphocyte subpopulations in SSNS and FSGS would imply an involvement of the immune system distinct from that in CNS.

Glomerular and tubular function in glycogen storage disease.

Urinary protein and calcium excretion were assessed in 77 patients with the hepatic glycogen storage diseases (GSD): 30 with GSD-I (median age 12.4 years, range 3.2–32.9 years), 25 with GSD-III (median age 10.5 years, range 4.2–31.3 years) and 22 with GSD-IX (median age 11.8 years, range 1.2–35.4 years). Inulin (Cinulin) and para-aminohippuric acid (CPAH) clearances were also measured in 33 of these patients. Those with GSD-I had significantly greater albumin (F=15.07,P<0.001), retinolbinding protein (RBP) (F=14.66,P<0.001),N-acetyl-β-d glucosaminidase (NAG) (F=9.41,P<0.001) and calcium (F=7.41,P=0.001) excretion than those with GSD-III and GSD-IX. GSD-I patients (n=18) also had significantly higherCinulin (F=5.57,P=0.009), butCPAH did not differ (F=0.77, NS). Renal function was normal in GSD-III and GSD-IX patients. In GSD-I,Cinulin (r=−0.51,P=0.03) and NAG excretion (r=−0.40,P=0.03) were inversely correlated with age, whereas albumin excretion was positively correlated with age (r=+0.41,P=0.03). RBP and calcium excretion were generally high throughout all age groups. Hyperfiltration in GSD-I is associated with renal tubular proteinuria that occurs before the onset of significant albuminuria. Deficiency of glucose-6-phosphatase within the proximal renal tubule may primarily cause tubular dysfunction, glomerular hyperfiltration being a secondary phenomenon.

Variability of urine albumin excretion in normal and diabetic children

The variability of urine albumin excretion (UAE) was studied in normal and diabetic children and, in addition, the best method of expressing the data was investigated. In 39 timed overnight urine samples from diabetic children, the urine albumin creatinine clearance ratio (CA/CC) was compared with the urine albumin creatinine concentration ratio (UA/UC), the urine albumin excretion rate (UAER) and the urine albumin concentration (UA). UA/UC predicted CA/CC (r=0.95) better than either UAER (r=0.83,P<0.02) or UA (r=0.90), 0.1>P>0.05). The within-individual and the between-individual variability in overnight UA/UC in 171 urine samples from 73 normal children was compared with that of 406 urine samples from 119 diabetic children, using a “random effects type 2 nested analysis of variance” model. Geometric mean (range) UA/UC (mg/mmol) in diabetic children, 0.55 (0.04–6.90), was greater than in normal children, 0.33 (0.05–2.10,P<0.01), and 18% of diabetics had a value of UA/UC above the normal range. Within-individual variance was the same in normals (0.12) and diabetics (0.12), but between-individual variance in diabetics (0.18) was much greater than in normals (0.03). These data show that within-individual observations for both normals and diabetics are highly but equally variable. Furthermore, from these data, it is possible to infer that a minimum of five estimations are necessary per individual to estimate the true mean value of urine albumin excretion with reasonable confidence.

Vascular endothelial growth factor stimulates embryonic urinary bladder development in organ culture.

To determine whether vascular endothelial growth factor A (VEGF) and its receptors are expressed during bladder development in mice when capillaries are forming, and whether exogenous VEGF might enhance the growth of endothelia and other types of bladder cells, using an embryonic organ‐culture model.

Effect of cyclosporin A on glomerular filtration rate in children with minimal change nephrotic syndrome

Cyclosporin A (CyA) is now commonly used in the management of children with steroid-dependent nephrotic syndrome. In order to assess nephrotoxicity related to CyA therapy, we measured glomerular filtration rate (GFR) on 123 occasions in 24 children with minimal change nephrotic syndrome receiving CyA. GFR was estimated from the plasma clearance of51chromium-EDTA every 3 months during CyA therapy of up to 27 months duration. There was a significant reduction in GFR after 3 months of CyA therapy [118±33 (SD) to 93±24 ml/min per 1.73 m2] but no further fall thereafter, although the reduction in GFR was sustained for the duration of CyA therapy. This reduction in GFR appeared to be reversible upon cessation of CyA, but careful monitoring of renal function is necessary in such patients to prevent the development of longer term nephrotoxic sequelae.

Urinary supersaturation of calcium oxalate and phosphate in patients with X-linked hypophosphatemic rickets and in healthy schoolchildren.

UNLABELLED Nephrocalcinosis (NC) is a complication of the treatment of X-linked hypophosphatemic rickets (XLHR). Some studies have found that treated patients have enteric hyperoxaluria caused by phosphate therapy and have implicated calcium oxalate, whereas others have found only calcium phosphate in renal biopsy tissue. AIM AND METHODS We aimed to study the urinary supersaturation of calcium oxalate and calcium phosphate and to determine whether these measures are risk factors for NC. We collected 24-hour urine samples from 20 patients (12 girls) with XLHR, mean +/- SD age 8.2 +/- 4.7 years, and from 79 age-matched members of a healthy control group prospectively. RESULTS The median 24-hour urine excretions of oxalate, phosphate, and citrate (mmol/1.73 m(2) per day) were significantly increased in patients compared with the control group (oxalate 0.38 vs 0.28, P =. 0012; phosphate 63.1 vs 25.8, P <.0001; citrate 4.18 vs 2.7, P =. 0002). However, no significant differences were seen in the calcium oxalate or calcium phosphate between patients and the control group. No significant differences were seen in 24-hour urine calcium or magnesium excretion between patients and the control group; however, 8 patients had hypercalciuria. A significant higher urine volume in patients compared with the normal group (826 mL/m(2) 24-hour vs 597 mL/m(2) 24-hour; P <.005) was found. Twelve patients had NC at the time of investigation, and although the oxalate excretion was significantly higher in these patients, no significant difference was seen in the relative supersaturation of calcium oxalate monohydrate (CaC(2)O(4).H(2)O) compared with the 8 without NC. CONCLUSIONS Although 24-hour urine oxalate and phosphate excretion are increased in treated patients with XLHR, there is no increase in the supersaturation of either calcium oxalate or phosphate. Determination of the supersaturation of calcium oxalate or calcium phosphate does not predict the development of NC in XLHR.

Anti-Neutrophil cytoplasmic antibodies in Kawasaki disease

Autoantibodies against components of neutrophil cytoplasm develop during adult vasculitic diseases such as Wegeners granulomatosis and microscopic polyarteritis, and they are predominantly of the IgG class. Similar but distinct antibodies have been described in children with Kawasaki disease and both IgM and IgG class antibodies are represented. This adds another clinically distinct childhood form of vasculitis to the adult forms in which autoantibodies to neutrophil cytoplasmic antigens have been detected.

Salivary excretion of endogenous proteins in nephrotic syndrome in children.

Abstract. Size and charge selectivity of capillary permeability in the salivary glands of nephrotic children were investigated by measuring salivary excretion of endogenous plasma proteins of different size and charge. We examined 10 children with steroid-sensitive nephrotic syndrome (SSNS) in relapse and subsequent remission, 11 with steroid-resistant nephrotic syndrome, and 11 healthy children (controls). Albumin [mol. wt. 66 kilodaltons (kDa), isoelectric point (pI) 4.9] was measured by radioimmunoassay, transferrin (mol. wt. 77 kDa, pI 5.9) and immunoglobulins IgG1 (mol. wt. 150 kDa, pI 7–9) and IgG4 (mol. wt. 150 kDa, pI <6) by enzyme-linked immunoabsorbent assay. In saliva, no significant differences were found between the four groups of children for any of the four proteins. Also, the saliva/plasma ratios of the four proteins were not different among the four groups. From these data, we conclude that in subjects with SSNS in relapse, neither size nor charge selectivity of salivary gland capillary permeability are affected.