The increasing importance of chronic rejection as a cause of renal allograft failure

A consequence of reducing early graft failure due to acute rejection has been that more patients are at risk of chronic rejection, something which has become an increasingly important cause of graft loss. We examine the graft survival rates and reasons for failure in our unit from 1981 to 1986. Patients were divided into two series according to treatment of acute rejection episodes. From 1983 onwards, by treating acute vascular (poor prognosis) episodes with antilymphocyte globulin (ALG), we have significantly improved the 6-month actuarial graft survival rate. However, the percentage of total graft failure due to chronic rejection in this second series has significantly increased. The need for greater understanding of the aetiology of chronic rejection, together with its present unsatisfactory treatment, is discussed.     

The increasing importance of chronic rejection as a cause of renal allograft failure

Abstract. A consequence of reducing early graft failure due to acute rejection has been that more patients are at risk of chronic rejection, something which has become an increasingly important cause of graft loss. We examine the graft survival rates and reasons for failure in our unit from 1981 to 1986. Patients were divided into two series according to treatment of acute rejection episodes. From 1983 onwards, by treating acute vascular (poor prognosis) episodes with antilymphocyte globulin (ALG), we have significantly improved the 6-month actuarial graft survival rate. However, the percentage of total graft failure due to chronic rejection in this second series has significantly increased. The need for greater understanding of the aetiology of chronic rejection, together with its present unsatisfactory treatment, is discussed.     

Retinitis pigmentosa and renal failure in a patient with mutations in INVS.

BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive disease, which is the most common genetic cause of end-stage renal disease in the first three decades of life. The disease is caused by mutations in the NPHP 1-5 genes, and is referred to as NPHP types 1-5, respectively. The association of NPHP and retinitis pigmentosa (RP) is known as Senior-Loken syndrome (SLS). The RP is associated with 10% of cases of NPHP types 1, 3 and 4, and all cases of NPHP type 5, but never in NPHP type 2, the infantile form of NPHP. The NPHP type 2 is distinguished from other types of NPHP by its early age of onset and by cystic enlargement of the kidneys. METHODS: Mutational analysis of all five NPHP genes was performed by exon sequencing in a child with infantile NPHP and RP from a consanguineous kindred. RESULTS: A homozygous mutation was identified in exon 13 of inversin (INVS) (C2719T, R907X) in this child. CONCLUSIONS: This is the first report of the presence of RP in a patient with NPHP type 2 and INVS mutations. This report now extends the association of RP with NPHP to NPHP type 2.     

Prevalence of chronic renal failure in adults in Delhi, India.

BACKGROUND: Chronic renal failure (CRF) is a debilitating condition responsible for high morbidity and mortality and is a financial burden on government and society. Because of its costs and the complexity of its treatment, proper care is available to very few patients in India. A community-based study has not been done to determine the prevalence of CRF in India. METHODS: We used a multi-stage cluster sampling method in the South Zones of Delhi. In each area, we first contacted the local social leader and explained the study and the medical information pamphlets. On pre-scheduled days, the study team canvassed the study zone. The individuals contacted responded to a detailed questionnaire, and had a physical examination, a dipstick urine test for albumin and sugar and a blood test for serum creatinine. A serum creatinine >1.8 mg% defined renal failure. A repeat test for serum creatinine was done after 8-12 weeks to confirm chronicity of renal failure. If it was >1.8 mg% after 3 months in the absence of reversible factors, CRF was diagnosed. The person found to have CRF was asked to attend a hospital renal clinic for further investigations and individualized management. RESULTS: A total of 4972 persons were contacted for the study. Their mean age was 42+/-13 years; 56% were males. Out of the 4972 who were initially approached, 4712 agreed to give the blood sample, and thus were included for the evaluation of CRF. CRF was found in 37 of them. Thus, the prevalence of CRF in that adult population was 0.785% or 7852/million. CONCLUSIONS: The prevalence of CRF in India makes it a serious problem in need of urgent efforts to contain it.     

Reduced venous responsiveness to endothelin-1 but not noradrenaline in hypertensive chronic renal failure.

BACKGROUND: Endothelin-1 (ET-1), acting mainly through the ET(A) receptor, is a potent endothelium-derived vasoconstrictor peptide. Circulating concentrations of ET-1 are increased in chronic renal failure (CRF) and may influence vascular tone. METHODS: We investigated dorsal hand vein responsiveness to local infusion of ET-1 and noradrenaline in 12 hypertensive and 12 normotensive CRF patients and in 12 age and sex matched control subjects. We also investigated dorsal hand vein responses to the ET(A) receptor antagonist, BQ-123, and the endothelium-independent vasodilator glyceryl trinitrate (GTN), in six patients with CRF. RESULTS: The dose of noradrenaline causing a 50% of maximal vasoconstriction was similar in the hypertensive (32+/-11 pmol/min) and normotensive (26+/-7 pmol/min) CRF patients and control subjects (21+/-6 pmol/min). Vasoconstriction to ET-1 (5 pmol/min) was similar in CRF patients as a whole (AUC 35+/-5%) and controls (32+/-4%; P=0.70). However, venoconstriction was significantly less in hypertensive (23+/-6%) than in normotensive CRF patients (48+/-8%; P=0.01). Overall, venoconstriction to ET-1 correlated inversely with mean arterial blood pressure in the CRF patients (R=-0.43, P=0.04). In addition, basal vein size was smaller, and plasma endothelin concentrations greater, in the hypertensive CRF group. However, infusion of BQ-123 or GTN did not cause venodilatation in these subjects. CONCLUSIONS: These studies are consistent with the hypothesis that elevated plasma ET-1 contributes to vascular tone, and elevated blood pressure, in hypertensive CRF patients, and is associated with vascular receptor downregulation consequent on the increased exposure to ET-1. The reduced vein size in CRF patients appears to be structural rather than functional in nature. Further long-term studies with endothelin antagonists are required to determine the pathophysiological role of ET-1 in the altered structure and function of blood vessels in patients with CRF.     

Hyperprolactinemia as a rare cause of hypertension in chronic renal failure

Chronic renal failure (CRF) is associated with a high risk for hypertension. An individualized treatment should be initiated after the diagnosis of hypertension and underlying etiology. Many metabolic and endocrinal abnormalities are encountered in CRF. We present an 11-year-old boy with CRF developing galactorrhea and hyperprolactinemia associated with α-methyldopa, defective dopaminergic control, and resistance to multi-antihypertensive therapy. Cabergoline, a dopamine receptor agonist, was effectively used in the treatment of hypertension. It is important to remember that sometimes treatment of an illness becomes the cause of this illness.     

C1q nephropathy in a child with a chromosome 13 deletion

C1q nephropathy (C1qNP) is a rare cause of childhood nephrotic syndrome (NS). We describe a child with retinoblastoma, lipomyelomeningocele and a chromosome 13 deletion who presented with massive proteinuria due to C1qNP. Despite steroid resistance, successful treatment of the NS was achieved with mycophenolate mofetil.     

Orofacial digital syndrome type 1: an underlying cause of chronic renal failure

Orofacial digital syndrome type 1 is condition which is characterized with, in addition to oral-facial and digital congenital anomalies, polycystic renal disease in most patient, and the prognosis is dependent on renal involvement in such patients. Our case was a 22-year-old patient who was presented with clinical picture of chronic renal failure, was started on hemodialysis and had took our attention due to oral, facial and digital anomalies in addition to polycystic renal disease.     

Occult lead intoxication as a cause of hypertension and renal failure

BACKGROUND.: The true incidence of lead (Pb) overload as a cause of chronicrenal failure (CRF) is unknown. Also, it is unclear if CRF perse could generate an increment in the body Pb burden. Most studiesof chronic Pb intoxication have been performed on cohorts orpatients with a past history of occupational exposure. Thereforewe studied the body Pb burden in CRF of known aetiology versusthose patients with CRF with gout and hypertension of unclearaetiology without a past history of Pb exposure. In additionwe studied patients diagnosed with essential hypertension. METHODS.: We studied 296 patients lacking a past history of Pb exposure,who were subdivided into four groups: group I (n=30), normalcontrol subjects; group II (n=104), patients with ‘essential’hypertension and normal renal function; group III (n=132), patientswith CRF of uncertain aetiology in association with hypertensionand/or gout, and group IV (n=30), patients with CRF of knownaetiology. The blood and urine Pb levels were assessed beforeand after an EDTA test. RESULTS.: No abnormal test results were obtained for patients in groupsI and IV. The EDTA test was abnormal in 16 patients (15.4%)in group II and in 74 patients (56.1%) in group III. A positivecorrelation was observed between plasma creatinine levels andpost-EDTA urinary Pb in group III, but not in group I. No correlationregarding plasma creatinine and the duration of hypertensionor gout were demonstrated. The bone Pb levels, measured in 12patients with pathological EDTA test results, were positivelycorrelated to the plasma creatinine levels. CONCLUSIONS.: A high percentage of patients with gout, hypertension, and CRFhave an excessive Pb burden, and about 15% of the patients diagnosedas ‘essential’ hypertensives also show high Pb burdens.It is remarkable that a history of overt Pb exposure was lackingin the whole study population.     

Low protein diets delay end-stage renal disease in non-diabetic adults with chronic renal failure.

BACKGROUND: The objective of this study was to determine the efficacy of low protein diets in delaying the need to start maintenance dialysis based on an analysis of published literature. METHODS: The search strategy involved a Medline and Embase search from January 1966 through to June 1999, congress abstracts (American Society of Nephrology since 1990, European Dialysis Transplant Association since 1985, International Society of Nephrology since 1987) and direct contacts with investigators. The selection criteria included randomized trials comparing two different levels of protein intake in adult patients suffering from moderate to severe renal failure, followed for at least 1 year. Patients with diabetic nephropathy were excluded. Seven trials were selected from 40 studies since 1975. A total of 1494 patients were analysed: 753 had received reduced protein intake and 741 a higher protein intake. The numbers of 'renal deaths' (defined as the need for starting dialysis, the death of a patient or kidney transplant during the trial) were collected. RESULTS: 242 renal deaths were recorded, 101 in the low protein diet and 141 in the higher protein diet group, giving an odds ratio of 0.61 with a 95% confidence interval of 0.46 to 0.83 (P=0.006). CONCLUSION: Reducing protein intake in patients with chronic renal failure reduces the occurrence of renal death by about 40% as compared with larger or unrestricted protein intake. The optimal level of protein intake cannot be confirmed from these studies.     

Lack of NPHP2 mutations in a newborn infant with Joubert syndrome-related disorder presenting as end-stage renal disease

A newborn infant with end-stage renal disease (ESRD) due to nephronophthisis (NPHP) developed episodes of tachypnea, alternating with apnea, and abnormal eye movements. Contrast-enhanced magnetic resonance imaging (MRI) of the midbrain demonstrated the characteristic appearance of molar tooth sign on axial images, consistent with the diagnosis of Joubert syndrome (JBTS). The DNA sequence analysis of the polymerase chain reaction (PCR) detected no mutations in the NPHP2 (INVS) gene in this child, suggesting that new mutant genes might be responsible for the early onset of ESRD in infantile NPHP with features of JBTS.     

Natural history of chronic renal failure: a reappraisal.

In this retrospective study we have analysed the rate of progression of renal insufficiency, ascertained from the slopes of the plot of inverse serum creatinine against time, of 102 patients with moderate to severe chronic renal failure (CRF). We have applied 'breakpoint' analysis of the slopes to identify changes in the rate of progression and attempted to determine the factors associated with these changes. Seventy-one patients were found to have progressive CRF, while the remaining 31 had stable or improving renal function. Of the parameters studied, using weighted least-squares analysis, proteinuria was the most significant predictor of progression (regression coefficient: -0.1775, P = 0.0075, adjusted r2 = 0.1059). A positive correlation was observed between proteinuria and diastolic blood pressure (DBP) (r = 0.336, P = 0.0054). Once the predictive value of proteinuria was taken into account, there was no difference in the progression rate between diagnostic groups, other than those patients with polycystic kidney disease who had a significantly faster rate of progression (P = 0.0037). In 49 patients, there was at least one change in the rate of progression with time. There was an inverse correlation between change in slope and a change in DBP (r = -0.352, P = 0.003). We conclude that changes in DBP are often associated with the frequent changes in the rate of progression of CRF. However, a causal link could not be established as in a large number of cases the two changes appeared to occur simultaneously in the absence of changes in antihypertensive therapy.     

Neuropathic bladder as a cause of chronic renal failure in children in developing countries

Neuropathic bladder is considered a threat to the kidneys if not managed appropriately. In this study, we report our experience with neuropathic bladder at King Abdulaziz University Hospital (KAUH) as a cause of chronic renal failure (CRF) in the pediatric age group. This retrospective study included all children diagnosed with neuropathic bladder who presented with moderate or severe CRF over a 4-year period from December 2000 to December 2004 [glomerular filtration rate (GFR) at presentation <50 ml/min per 1.73 m²]. Fifteen patients were diagnosed with neuropathic bladder; group A consisted of ten patients with spina bifida and one with sacral agenesis and group B consisted of four patients with nonneurogenic neurogenic bladders (NNNB). The mean age±SD at presentation was 6.2±3.8 years, GFR was 24.2±12.4 ml/min per 1.73 m², and creatinine was 289.9±253.2 μmol/l. There were no differences in the age at presentation to a pediatric nephrologist or the degree of renal failure at presentation between the two groups. Clean intermittent catheterization (CIC) was not started in all patients before presentation to KAUH, except in two children. Five children required dialysis as they were in end-stage renal failure (ESRF). All except one received peritoneal dialysis (PD). Their mean age at the start of dialysis was 10.8±1.7 years. Neuropathic bladder due to spina bifida or NNNB is an important cause of CRF in developing countries. There was a considerable delay in the diagnosis of NNNB and a significant delay in starting CIC in all neuropathic patients.     

Acute renal failure in a patient suffering from chronic alcoholism.

Introduction Urinary tract infections (UTI) are common in adults and areknown to cause deterioration in renal function in patients withchronic renal impairment, solitary kidneys and renal transplants.Acute non-obstructive pyelonephritis is rarely considered inthe differential diagnosis of acute renal failure (ARF), especiallyin patients with little or no evidence of previous kidney disease.Diagnosis is particularly difficult if the infection is asymptomatic.Chronic alcohol abuse increases the risk of ARF in unobstructedacute pyelonephritis [1] and is a rare cause of renal papillarynecrosis [2,3]. We present an unusual case of asymptomatic acute pyelonephritisin combination with renal papillary necrosis in an otherwisewell individual with a history of substantial alcohol abuse. Case A 62-year-old man was admitted to another hospital with an 8week history of increasing dyspnoea and lower limb oedema. Hehad no     

Human SA gene Pst1 polymorphism and chronic renal failure: results of the family-based study.

BACKGROUND: Because of the heterogeneous aetiology of kidney diseases, interactions between multiple genetic and environmental factors are thought to be involved in the process of progression to end-stage renal disease (ESRD). Raised blood pressure remains a well-established, independent risk factor for a more rapid decline of renal function in various kidney diseases. The aim of the study was to investigate the role of the human SA gene Pst1 polymorphism in the development and/or progression of chronic renal failure (CRF). METHODS: This polymorphism was genotyped in a group of 247 family trios (offspring affected with end-stage renal disease, and both parents): 120 with primary chronic glomerulonephritis, 80 with interstitial nephritis, and 47 with diabetic nephropathy. Transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected offspring. RESULTS: SA gene Pst1 allele transmission did not differ from random proportion of 50:50, with no significant variation in the slope of reciprocal serum creatinine over time between patients with SA Pst1 A1A1, A1A2, and A2A2 genotypes. In addition, no impact of this marker on the rate of progression of CRF in the course of diabetes mellitus, interstitial nephritis, and chronic glomerular nephritis was shown. CONCLUSION: Results of the study suggest no major role of SA gene polymorphism in promoting renal damage. However, the limited numbers of patients having both parents alive included in the analysis might have resulted in insufficient power to detect a minor impact of this polymorphism, especially if such effect is confined to a certain aetiology of CRF.     

Impact of chronic allograft nephropathy and subsequent modifications of immunosuppressive therapy on late graft outcomes in renal transplantation.

BACKGROUND: Chronic allograft nephropathy (CAN) is the leading cause of organ failure in renal transplant recipients. We retrospectively evaluated the impact of varying immunosuppression in CAN patients on long-term graft survival. METHODS: We retrospectively analysed 158 cyclosporin (CsA)-treated renal transplant recipients with biopsy-proven CAN with follow-up of >1 year. Immunosuppression remained unchanged in 75 (NOVAR) and was modified in 83 patients (VAR). In 36.1% of VAR patients, it was increased; in 63.8%, the addition of other immunosuppressants was associated with a 20% reduction in or withdrawal of CsA. A regression model, for creatinine clearance (CrCl) slope analysis after therapy variation, and Cox's analysis were applied. RESULTS: In VAR patients, two-phase regression did not show a correlation between the inflection point in the CrCl slope and treatment variation. Changing immunosuppression gave a borderline advantage in long-term graft survival compared with NOVAR (P = 0.088). In univariate analysis, severe histological lesions, proteinuria >0.5 g/day and CrCl <25 ml/min at biopsy correlated with poor graft outcome (P = 0.0009). In multivariate analysis, only proteinuria and low CrCl remained significative. Stratifying histological lesions in relation to therapy variation showed that severe lesions significantly decreased survival in both VAR and NOVAR groups; however, the highly negative impact of severe lesions in NOVAR patients on graft survival [relative risk (RR) 3.602] was reduced in VAR patients (RR 1.951), with a 10 year graft survival since biopsy of 0.16 vs 0.34 (P = 0.0001). CONCLUSIONS: In transplant patients with CAN, variation of immunosuppression can reduce the negative impact of severe chronic lesions.     

Association of glutathione S-transferase M1 and T1 gene polymorphism with oxidative stress in diabetic and nondiabetic chronic kidney disease

Background and Objective: Glutathione S-transferases (GSTs) belong to a family of ubiquitous and multifunctional enzymes that work as one of the endogenous antioxidants in our body. This study was designed to look into the association of GST polymorphism with oxidative stress in both diabetic and nondiabetic chronic kidney disease (CKD). Design and Methods: Three groups of patients (50 in each): diabetics without CKD (DM), diabetic CKD (DM-CKD), and nondiabetic CKD (NDM-CKD) and 50 age- and sex-matched healthy controls were recruited. Genotyping was done for GSTM1 and GSTT1 genes using a multiplex polymerase chain reaction. Serum GST and malondialdehyde (MDA) as a marker of oxidative stress were measured spectrophotometrically. Results: Based on genotyping, subjects were categorized as GSTM1+/GSTT1+, GSTM1?/GSTT1+, GSTM1+/GSTT1?, and GSTM1?/GSTT1?. Serum GST levels were lower among subjects with deletion in one/both GST genes, whereas MDA levels were found to be correspondingly raised. A negative correlation for MDA versus GST levels was observed among genotypes with one/both gene deletions. Presence of GSTM1+/GSTT1? and GSTM1?/GSTT1? was significantly higher among patients with CKD in both diabetics and nondiabetics. Interpretations and Conclusions: GSTM1 and GSTT1 deletions singly or together were associated with lower GST levels and higher oxidative stress in both diabetic and nondiabetic CKD. Interestingly, GSTT1 deletion appears to be associated with both diabetic and nondiabetic CKD irrespective of the GSTM1 status.